More than fifty years ago, Borrel presented his hypothesis of viral origin of cancer based primarily on analogies. Since then, although an enormous amount of material on this subject has accumulated, much of it has been contradictory and it has appeared to be impossible to arrive at any clear cut concept of the role of viruses in the pathogenesis of tumors. However, it seemed that an attempt to correlate most of the data with information furnished by the study of chemical carcinogenesis in the light of the concept of cancer as a complex hierarchic disease might be of some value for an initial simplification of the problem. (293, 312) (Note 2)

Some theoretical considerations have helped in systematizing the data and in indicating the probable limits of viral intervention in carcinogenesis. Just as with chemical carcinogens, it could be assumed that virus intervention may bring to bear multiple factors. An analysis of the processes which occur under viral influence indicates that this hypothesis is plausible.

Even more than chemical carcinogens, viruses are able to act only at certain levels of organization. Their intracytoplasraatic and often intranuclear development conditions the intervention of these agents at these levels. Fundamental differences in carcinogenic effect could be expected if viruses are able to influence the subnuclear levels, or the nucleus, or, on the other hand if their activity is limited to the cytoplasm. This view has permitted us to understand the striking difference in influence exerted by various viruses which, although recognized by any worker in the field, has not been the subject of any special consideration.

Two Types Of Carcinogenic Effects

The difference lies in the time needed for a virus to produce carcinogenic effects. Inoculation of fowls with purified Rous sarcoma virus, for instance, has been seen to produce a clear cut, immediate effect. Changes have been recognized within 48 hours at the site of inoculation. They take place in the nuclei of fibrocytes and consist of swelling, appearance of a more distinct nuclear membrane, cleared nucleoplasm, marginatum of chromatin and one or more enlarged nucleoli. In as few as one or two days, cytoplasmic changes are also evident. There is manifest basophilia with swelling of the cell which becomes greatly enlarged. Concomitant with these changes, the abnormal cells invade the fibrillar tissue. The tumor which develops has the character of the classical spindle cell Rous sarcoma.

Thus a cancerous tumor in the invasive stage, with typical nuclear and cytoplasmic cell characters, is induced in only a few days at the site of inoculation. This is characteristic of one type of viral carcinogenesis, the extremely active one. Integrated in the concept of complex carcinogenesis presented above, it would mean that the entire series of changes—from those at the lowest level which determine the cancerous character to the cytoplasmic changes which produce the proliferative, invasive cancer—has been achieved by the virus in this short time. In fact, this tumor grows rapidly, is palpable even at the fifth day and fatal in two to three weeks.

Almost diametrically opposed to this type of carcinogenesis are tumors which represent another type of virus intervention, such as certain mammary cancers in mice. Viruses that produce such tumors can be obtained from various organs, even from those of animals without apparent tumors. They induce the appearance of tumors but only under very characteristic circumstances. Preferably introduced in the first days of life—subcutaneously, intraperitoneally or even orally—they will produce their effect only after many months or even after one or two years, as tumors of a specific organ, such as the mammary gland, for example. However, such tumors appear almost only in females who have had one or more pregnancies. In this case, the virus acts only upon highly differentiated cells and acts independently of the site of inoculation. The extremely long period without manifestation, the fact that the virus can be found to some extent in various organs which show no change, and the specific localization in a highly differentiated organ such as the mammary gland, would indicate that the carcinogenic intervention of the virus is highly related to a specific character of these cells, their particular differentiation. This would place virus intervention at the cytoplasmic level where differentiation occurs.

Under this interpretation, the length of time necessary for tumor appearance would be related to the time needed for a natural evolution of the mammary cells to the point where they are sufficiently differentiated. It appears probable that this length of time corresponds to that needed by abnormal hierarchic entities of the mammary cells to have arrived, independently of the virus, at a state corresponding to that of precancer or noninvasive cancer. Intervention of the virus at the cytoplasmic level would then transform the relatively advanced but still noninvasive cancer cells into invasive cancer cells. Viruses would act, in this case, as cytoplasmic carcinogens.

These two types represent the extremes of carcinogenesis in which viruses play a role. They help to interpret many of the other data furnished by experiments. For didactic purposes, we shall regard as "broad scale" viruses those which act from very low to high levels of the organism, and as "cytoplasmatic" those which act at the higher cellular level only.

Some of the rapidly acting broad scale viruses will induce evolving tumors in a much shorter time than any known chemical or physical carcinogen, a fact that can be interpreted as meaning that these viruses are more capable of inducing not only the cytoplasmatic carcinogenic changes but also the entire scale of preparatory changes leading to invasive cancer. Viruses differ from the usual active chemical carcinogens in their special capacity to induce changes easily at the cytoplasmic level where they are particularly capable of multiplying and acting. This would contrast with most chemical agents which generally have low carcinogenic activity at the cellular level. Chemical and virus carcinogenic activity would complement each other. This is in accord with experiments of Russian scientists, which have shown that cultures of cells treated with methylcholanthrene in vitro become highly carcinogenic when inoculated in animals if a cancerous virus is also added.

This view of the activity of cytoplasmatic viruses at the higher cellular level, as contrasted with many chemical carcinogens usually more active at lower levels, appears also to be in agreement with the experiments of Rous and Kidd (69, 70) which demonstrated the capacity of coal tar extracts to localize the Shope papilloma virus. The high cytotropic character of this virus is well known. It would easily act upon cells already transformed from normal into noninvasive form by chemical agents which are active at the lower levels. These chemical agents thus "localize" the viral activity. This is in accord with the ability of chemical agents in the Rous and Kidd experiments to increase the percentage of invading carcinomas as compared to the papillomas present. According to the view presented above, the papilloma as a benign tumor would represent changes similar to those seen in cancer but limited exclusively to the higher levels, without cancerous entities at the lower levels. The addition of an agent with a broad scale of carcinogenic activity, that is, acting also at the lower levels, such as the chemical agent, would give the resulting lesion the entire cancerous scale, that is, the character of malignancy.

The integration of viral carcinogenesis in the concept of cancer as a complex condition and recognition of the two extreme types of viral carcinogenic activity permits us to understand the reserve of most authors over the viral etiology of cancer. For instance, many have refused to accept as a carcinogenic factor the virus shown by Bittner (71) to be present in maternal milk and to influence the appearance of mammary carcinoma in mice. The refusal is based upon comparison of this virus with that of the first type seen in fowl tumors. With the systematization presented above and the concept of broad scale and cytoplasmatic carcinogenic viruses, this reason is not valid. Furthermore, a carcinogenic virus should not be considered to be the indispensable factor able to induce proliferative cancer in animals which usually have a virus cancer. This would explain why, in certain breast carcinomas in mice, a viral agent could never be found. (72)

The specific capacity of a virus to act upon a differentiated cytoplasm explains the fact that a virus may be widely distributed among organs but does not induce tumors except in special cells. Previous preparatory changes seem necessary for the cytoplasmatic virus to intervene. This is in accord with a low incidence of tumors in certain strains of mice despite an abundant presence of the "milk factor" virus. (73)

These facts shed a new light on the entire problem of the relationship between viruses and tumors. Viruses can multiply in organisms without inducing cancer. The virus of mammary carcinoma in mice can be transmitted to females through spermatozoa and can be found in large amounts throughout the organism. The virus is present a long time before any cancerous lesions are seen and is present in organs that will never have tumors and even in animals that never develop cancer. The development of this virus, like all viruses, takes place in the cell cytoplasm which does not necessarily mean the induction of carcinogenesis as long as other factors are not present. No tumors appear as long as the cell has not undergone the prior changes required if the cytoplasmatic carcinogenic effect is to take place. Without the previous changes, the virus will not influence the cell any more than many other noncarcinogenic viruses. It is only in the presence of an advanced cellular change that the virus will produce an invasive cancer.